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PDBsum entry 5hpm
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Immune system
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PDB id
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5hpm
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Contents |
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213 a.a.
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216 a.a.
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12 a.a.
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PDB id:
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| Name: |
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Immune system
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Title:
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Cetuximab fab in complex with cyclic linked meditope
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Structure:
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Cetuximab fab light chain. Chain: a, c. Engineered: yes. Cetuximab fab heavy chain. Chain: b, d. Engineered: yes. N-acetyl-l-cysteine, cyclic amidated, acetylated linked meditope. Chain: e, f.
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Source:
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Mus musculus, homo sapiens. Mouse, human. Organism_taxid: 10090, 9606. Expressed in: unidentified. Expression_system_taxid: 32644. Synthetic: yes. Synthetic construct. Organism_taxid: 32630
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Resolution:
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2.67Å
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R-factor:
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0.190
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R-free:
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0.232
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Authors:
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K.P.Bzymek,J.C.Williams
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Key ref:
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K.P.Bzymek
et al.
(2016).
Cyclization strategies of meditopes: affinity and diffraction studies of meditope-Fab complexes.
Acta Crystallogr F Struct Biol Commun,
72,
434-442.
PubMed id:
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Date:
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20-Jan-16
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Release date:
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15-Jun-16
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PROCHECK
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Headers
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References
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No UniProt id for this chain
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Acta Crystallogr F Struct Biol Commun
72:434-442
(2016)
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PubMed id:
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Cyclization strategies of meditopes: affinity and diffraction studies of meditope-Fab complexes.
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K.P.Bzymek,
Y.Ma,
K.A.Avery,
D.A.Horne,
J.C.Williams.
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ABSTRACT
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Recently, a unique binding site for a cyclic 12-residue peptide was discovered
within a cavity formed by the light and heavy chains of the cetuximab Fab
domain. In order to better understand the interactions that drive this unique
complex, a number of variants including the residues within the meditope peptide
and the antibody, as well as the cyclization region of the meditope peptide,
were created. Here, multiple crystal structures of meditope peptides
incorporating different cyclization strategies bound to the central cavity of
the cetuximab Fab domain are presented. The affinity of each cyclic derivative
for the Fab was determined by surface plasmon resonance and correlated to
structural differences. Overall, it was observed that the disulfide bond used to
cyclize the peptide favorably packs against a hydrophobic `pocket' and that
amidation and acetylation of the original disulfide meditope increased the
overall affinity ∼2.3-fold. Conversely, replacing the terminal cysteines with
serines and thus creating a linear peptide reduced the affinity over 50-fold,
with much of this difference being reflected in a decrease in the on-rate. Other
cyclization methods, including the formation of a lactam, reduced the affinity
but not to the extent of the linear peptide. Collectively, the structural and
kinetic data presented here indicate that small perturbations introduced by
different cyclization strategies can significantly affect the affinity of the
meditope-Fab complex.
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Links
